The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model
© Ben-Shachar et al.; licensee BioMed Central Ltd. 2012
Received: 2 October 2012
Accepted: 4 December 2012
Published: 19 December 2012
Acetaminophen (N-acetyl-para-aminophenol) is the most widely used over-the-counter or prescription painkiller in the world. Acetaminophen is metabolized in the liver where a toxic byproduct is produced that can be removed by conjugation with glutathione. Acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for 56,000 emergency room visits per year. The standard treatment for overdose is N-acetyl-cysteine (NAC), which is given to stimulate the production of glutathione.
We have created a mathematical model for acetaminophen transport and metabolism including the following compartments: gut, plasma, liver, tissue, urine. In the liver compartment the metabolism of acetaminophen includes sulfation, glucoronidation, conjugation with glutathione, production of the toxic metabolite, and liver damage, taking biochemical parameters from the literature whenever possible. This model is then connected to a previously constructed model of glutathione metabolism.
We show that our model accurately reproduces published clinical and experimental data on the dose-dependent time course of acetaminophen in the plasma, the accumulation of acetaminophen and its metabolites in the urine, and the depletion of glutathione caused by conjugation with the toxic product. We use the model to study the extent of liver damage caused by overdoses or by chronic use of therapeutic doses, and the effects of polymorphisms in glucoronidation enzymes. We use the model to study the depletion of glutathione and the effect of the size and timing of N-acetyl-cysteine doses given as an antidote. Our model accurately predicts patient death or recovery depending on size of APAP overdose and time of treatment.
The mathematical model provides a new tool for studying the effects of various doses of acetaminophen on the liver metabolism of acetaminophen and glutathione. It can be used to study how the metabolism of acetaminophen depends on the expression level of liver enzymes. Finally, it can be used to predict patient metabolic and physiological responses to APAP doses and different NAC dosing strategies.
KeywordsAcetaminophen Hepatotoxicity Mathematical model Glutathione NAPQI
Acetaminophen (N-acetyl-para-aminophenol, APAP or paracetamol) is the most widely used over-the- counter and prescription painkiller in the world. While safe at therapeutic doses of up to 4 grams per day for adults, acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for some 56,000 emergency room visits, 2,600 hospitalizations and nearly 500 deaths annually[2, 3].
N-acetylcysteine (NAC) can be an effective antidote for APAP poisoning. NAC limits hepatotoxicity by increasing GSH synthesis in the liver. Current protocols recommend treating patients with an initial dose of 150 mg/kg NAC, infused over a period of an hour, upon hospitalization, followed by decreasing amounts of NAC infused over the next 20 hours. Fatal liver damage can be prevented if the initial dose of NAC is administered within 8-12 hours of an APAP overdose. This antidote dosage regime has been developed empirically over a period of many years based on outcomes from clinical cases. It is not known whether the current NAC treatment protocol is optimal.
The metabolism of APAP has been well-studied and the distributions of its metabolites in the plasma and urine of humans are well-documented[4, 6, 7], as are the hepatic values in mice and rats. What has been lacking is an integrated and quantitative understanding of the kinetics of APAP metabolism, of how APAP dosage affects NAPQI synthesis and GSH concentrations in the liver, of how NAC stimulates the synthesis of GSH, and of how the dosage and timing of NAC affect detoxification of NAPQI. In this paper we develop a mathematical model for APAP metabolism that allows us to study, in silico, how various doses of APAP are metabolized and whether or not a dose exceeds the capacity of the liver to synthesize sufficient GSH. In order to study how the metabolism of APAP affects GSH concentration and resynthesis, we have connected the model depicted in Figure1 to our extant model of glutathione metabolism. This enables us to examine the effect of GSH synthesis capacity on the ability of hepatocytes to detoxify NAPQI, the accumulation of NAPQI-induced liver damage, and the effects of different doses and timing of NAC in emergency departments.
Remien et al. recently developed a mathematical model to estimate overdosage of APAP based on indicators of liver damage (blood levels of aspartate aminotransferase, alanine aminotransferase and the international normalized ratio of prothrombin time) that are measured upon admission to hospital emergency departments. In a retrospective study, this model was able to accurately predict whether the overdose would lead to fatal liver damage. Our model is complementary to the work of since it focuses on the detailed biochemical mechanisms by which of APAP is detoxified in the liver under both normal and overdose situations.
Names used for Variables
APAP in the gut
APAP in the plasma
APAP sulfonate in the plasma
APAP glucoronidate in the plasma
NAPQI-GSH complex in the plasma
APAP in the liver
APAP sulfonate in the liver
APAP glucoronidate in the liver
NAPQI in the liver
covalent binding of NAPQI in the liver
NAPQI-GSH complex in the liver
GSH in the liver
APAP in the tissue
APAP sulfonate in the tissue
APAP glucoronidate in the tissue
APAP in the urine
APAP sulfonate in the urine
APAP glucoronidate in the urine
NAPQI in the urine
NAPQI-GSH complex in the urine
Parameters ( μ M, μ M/hr,/hr)
Compartment volumes (liters)
Transport parameters (μ M/hr)
APAP from gut to liver
APAP from plasma to tissue
APAP from tissue to plasma
APAP from plasma to liver
APAP from liver to plasma
sulfonate from liver to plasma
sulfonate from tissue to plasma
glucoronidate from liver to plasma
glucoronidate from tissue to plasma
NAPQI-GSH conjugate from liver to plasma
APAP from plasma to urine
sulfonate from plasma to urine
glucoronidate from pasma to urine
NAPQI-GSH conjugate from plasma to urine
logistic growth (h r−1)
maximum hepatocyte number
(. 213)10−4. 2
cell death rate due to NAPQI (h r−1μ M−1)
removal of dead hepatocytes (h r−1)
Biochemical Parameters ( μ M, μ M/hr,/hr)
V max in liver
V max in tissue
V lpaps (synthesis liver)
k lpaps (linear removal)
V tpaps (synthesis tissue)
k tpaps (linear removal)
V(l/t)UGT=VUGT1 + VUGT2 + VUGT3 + VUGT4
V max in liver
V max in tissue
V max in liver
V max in tissue
V max in liver
V max in tissue
V max in liver
V max in tissue
Absorption and dosing
APAP is absorbed from the gut into the portal circulation which flows into the liver. In our model, our oral doses are deposited in the gut compartment and then removed and put into the liver with linear kinetics. In the half life for gastric emptying was calculated to be 7 minutes for oral liquid doses and overnight fasting. We take the linear rate constant to be 4μ M/hr, which gives a half-life of approximately 10 minutes, since absorption will be slower with pills and non-fasted state. Most of the dose is absorbed in 30 to 60 minutes. The bioavailability of APAP is known to vary considerably depending on age, method of administration, and gut contents. An early study measured an average bioavailability of 79% and a recent study found a range 63%–89%. We assume that the bioavailability of a dose is 75%. A standard therapeutic dose is variously reported as 1000 mg or 20 mg/kg. In our model, we assume a 60 kg individual and a dose of 20mg/kg, which would make that standard dose 1200 mg. To convert those values to molarity in the gut we assumed a gut volume of 1 liter; then a 20 mg/kg dose (the typical therapeutic dose) produces a gut concentration of 6000 μ M, assuming 75% bioavailability.
Allosteric activation, including substrate activation, of P450 enzymes has been extensively documented[17–19]. We have included substrate activation (the Hill term on the right) and found that if we omitted this substrate activation then the cytochrome oxidase reactions did not produce enough NAPQI at high overdoses.
Glutathione synthesis and metabolism
We use a previously published model of liver glutathione metabolism. That model is connected to the model for APAP metabolism described here by adding the reaction by which GSH conjugates NAPQI via the enzyme GST. This enables us to study how different doses of APAP decrease liver GSH and how that affects the formation of NAPQI. We take the K m of GST for GSH to be 5200 μ M, midway between the values 4500 and 5600, K m = 15μ M for NAPQI, and V max = 72,000μ M/hr.
NAPQI is believed to exert its toxic effects by binding covalently to liver proteins leading to protein denaturation and necrosis of liver cells[6, 26, 27]. We model the reaction as linear and reversible because covalent binding of NAPQI gradually declines after eight hours[28, 29].
The rate at which functional hepatocytes are damaged is proportional to the product of the number of functional hepatocytes and the concentration of covalent binding of NAPQI. We use the differential equations for the rate of change of the number of living hepatic cells and the rate of change of the number of damaged cells from.
There are few measurements of overall transport rates of the metabolites between the compartments of the model. We chose to make all transport rates linear and adjusted them so that the measured APAP, APAP-S, APAP-G, and NAPQI-GSH concentrations in the plasma and the urine were as measured in the literature[4, 6, 11, 30–32]. Values of the transport coefficients are given in Table2.
Model comparison to experimental data
Effect of chronic dosing
The recommended therapeutic dose of APAP is 1000 mg not more than four times per day ([33, 34]). In Australia and new Zealand, the recommended dose is 500 to 1000 mg every four to six hours, not to exceed 4000 mg per day. In the USA, the maximum dosage per day recommended by the manufacturer (MacNeil Consumer Healthcare) was reduced from 4000 mg (eight 500 mg pills) to 3000 mg (six 500 mg pills) in 2011.
Although high doses of APAP are well known to be associated with increased risk of liver failure, chronic exposure to standard therapeutic doses is also not without risk. Forget et al. report on two cases of acute liver failure after 3 and 10 days of therapeutic APAP treatment, respectively, in patients with liver steatosis. Nuttall et al. studied the effect of chronic ingestion of therapeutic doses of APAP (1 gram, 4 times per day, for 2 weeks) on serum antioxidant capacity, and found a gradual and progressive decline to a level about 85% of control value. Part of the antioxidant capacity of serum is due to the presence of GSH and the reduced capacity could be associated with a general reduction in GSH due to its conjugation with NAPQI. Watkins et al. studied the effect of chronic APAP ingestion (using the same protocol of 1000 mg every 6 hours for 14 days) on liver damage as measured by elevation of serum alanine aminotransferase (ALT). They found ALT elevations of up to 8 times the upper limit of normal in 8% of participants, and three times the upper limit of normal in 39% of participants. This study was stopped early due to the frequency and magnitude of the elevation in ALT in the treatment group relative to controls, although none of the participants expressed symptoms of liver disease. In a prospective study, Sabate et al. estimated the incidence of acute liver injury due to therapeutic dosages of APAP to be about 10 per million user-years. These studies show that chronic usage of APAP at recommended therapeutic levels probably does mild liver damage and may be associated with a reduction in GSH levels that compromise antioxidant defense capacity.
Effect of drugs that affect P450 activity
The toxicity of acetaminophen is due to the action of several P-450 cytochromes (CYPs) that catalyze the synthesis of NAPQI from APAP. The activity of these enzymes is enhanced by a variety of chemicals, including caffeine[40, 41] and anticonvulsant drugs, and it is well known that co-ingestion of these drugs with APAP can greatly enhance the toxicity of APAP.
A relationship between the consumption of ethanol and the toxicity of APAP has also long been known. In rats and mice, chronic exposure to alcohol causes an increased expression of CYP-2E1 and increases the activity of the enzyme 5- to 7-fold[44, 45]. In humans the effect is much less dramatic, and alcohol consumption causes a transient two-fold induction of CYP-2E1 ([43, 46]). The role of alcohol in enhancing the toxic effects of APAP is variable and acute alcohol doses may have different effects on P-450 induction than chronic exposure to alcohol. Exposure of cultured human hepatocytes to alcohol increased the expression of CYP-2E1 and CYP-3A3/4 up to 6-fold, but the effect appeared to be individually variable.
Prescott has suggested that increased APAP toxicity in the presence of alcohol may occur only when the liver is already compromised by other factors. Our finding that there is only a small increase increase in covalent binding after a therapeutic dose, even with a four-fold increase in CYP P-450 activity supports this idea.
Effects of polymorphisms in glucoronosyl transferases
There are two reasons to expect that the glucoronosyl tranferase enzymes may be crucial for preventing liver damage. First, as we have shown above in Figures4 and5, the sulfation reaction saturates at fairly low APAP doses because of the low concentration of PAPS. Second, although the conjugation of the toxic intermediate NAPQI by glutathione is an important protective mechanism, it occurs after the production of NAPQI, while glucoronidation removes APAP before the production of NAPQI. Furthermore, a large number of genetic variants have been described in the UGT genes that are due to mutations in both the coding and regulatory regions of the genes[48–53]. These genetic variants are common and can have profound effects on the APAP glucoronidation capacity of the liver. For instance, Fisher et al. found up to 7-fold differences in the rates of APAP glucoronidation in a sample of 20 human livers, and Court et al. found 15-fold inter-individual variability in APAP glucoronidation rates in liver microsomal fractions.
Glutathione depletion and N-acetylcysteine rescue
We also simulated the effect on hepatic GSH level and functional hepatocytes of two other dosing protocols. In protocol 2, we give 3.6 mM of NAC per hour for 10 hours beginning 2 hours after the 22 g APAP dose. Thus, the total amount of NAC infused was identical to the standard amount given in a 1 hour-infusion (protocol 1). Our simulations (red dashed curve in Figure12) show that protocol 2 does better than protocol 1: the red dashed curves are higher than the black dashed curves. Finally, we simulated the NAC dosing protocol recommended in, which we refer to as protocol 3. This protocol consists of infusing half the 36 mM NAC dose over a 1-hour period starting at 2 hours after the APAP dose, followed by 1/6 of the dose over the next 4-hour period and then 1/3 of the dose over an additional 16 hours. The blue dashed curves in Figure12 show the time course of GSH (Panel A) and the time course of functional hepatocytes (Panel B) for protocol 3. Protocol 3 is substantially better than protocol 2, which is better than protocol 1.
Predicted death or recovery
We have created a whole body model of acetaminophen transport and metabolism that includes the details of the biochemical pathways of acetaminophen metabolism in the liver and peripheral tissues. The model was based as much as possible on parameters from the biochemical literature. When compared to experimental and clinical data on the accumulation of the byproducts of acetaminophen metabolism, APAP-S, APAP-G, and NAPQI-GSH, in the plasma and in the urine of humans, the model gives accurate predictions (see Figures2,3,4 and5).
We connected the whole body model of acetaminophen metabolism to our previously constructed model of glutathione metabolism so that we could study the depletion of GSH after APAP doses of various sizes (Figure6). We found that therapeutic doses decrease liver GSH by only modest amounts (10%), but that overdoses of 10 grams or more severely deplete liver GSH (Figure6). In addition, chronic therapeutic doses do deplete liver GSH significantly (30%; Figure7). Futhermore, it takes more than two days for the liver to synthesize enough GSH to bring concentrations back to normal (Figure9). Our model results correspond well with measurements of plasma GSH after doses of various sizes (Figure6).
Acetaminophen is toxic to hepatocytes because of the production of the intermediate, NAPQI, by cytochrome P450 enzymes. Thus it is not surprising that compounds that increase the activity of the P450 enzymes, such as caffeine[40, 41] and anticonvulsant drugs also make APAP more hepatotoxic. There is also a connection between alcohol consumption and APAP hepatotoxicity, and again the presumed mechanism is an increase in activity of one or more P450 enzymes[46, 47]. We show in Figure8 that the effect of increasing the activity of the P450 enzymes is highly nonlinear. At low doses of APAP there is little effect while the hepatotoxicity increases rapidly at high doses.
In Section “Effects of polymorphisms in glucoronosyl transferases” we showed that polymorphisms in the glucoronosyl transferase enzymes can have a large effect on the amount of liver damage caused by moderate overdoses of APAP. Figure9 shows that under normal circumstances, a 10 g dose does not cause much liver damage. However, if polymorphisms in the glucoronosyI transferases reduce the V max values to 50% of normal then the number of hepatocytes drops to about 75% of normal after 20 hours. And, if polymorphisms in the glucoronosyI transferases reduce the V max values to 10% of normal then the number of hepatocytes drops to about 10% of normal after 20 hours. Thus, liver damage is quite sensitive to polymorphisms in the glucoronosyl transferases and this probably explains some of the variation in patient response.
It is known that the ability to detoxify APAP varies greatly among different animal species. In particular, cats are acutely sensitive to APAP hepatotoxicity because they do not glucoronidate APAP well in their livers. Because our model includes the metabolic pathways in the liver, after some modifications, it can be used to study APAP metabolism and toxicity in other species, a task that we plan to take up in the future.
The standard antidote for APAP overdoses given in Emergency Departments is N-acetylcysteine (NAC) which is given to increase GSH production. Our model confirms the clinical observation that NAC rescue within 8 hours of overdose is usually successful in preventing liver failure (Figure11). We take liver failure to be equivalent to less than 30% remaining hepatocytes as suggested in. We then used the model to study different dosing strategies and found that modest differences result from different dosing strategies as long as they are started early enough (Figure12).
An important check on our model was to compare it’s predictions on patient outcomes to the empirical data and modeling results presented in. Both our model and theirs predict accurately death or recovery in the 53 patients studied by (Figure13). Their model, which is much simpler than ours in that it does not contain detailed liver biochemistry, is sufficient for predicting patient outcomes. The purpose of our larger model is to provide a platform for experimentation with NAC dosing protocols, and with the effects of genetic polymorphisms, expression levels of enzymes, diet, the depletion of GSH, and the effects of environmental enzyme activators or inhibitors such as caffeine and alcohol.
This research was partially supported by NSF grants DMS-0616710(MR, HFN) and EF-1038593(HFN, MR) and NIH grant R01 ES019876 (D. Thomas).
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